A history of early life stress is an important risk factor for depressive and anxiety disorders and a range of poor health outcomes. Alterations in the neuroendocrine and immune systems, key pathways in the neurobiological response to stress, are involved in the stress-induced changes that are linked to depressive and anxiety disorders. Recent work indicates that epigenetic modifications to genes in these pathways may be a central mechanism of the effects of childhood adversity. Gene methylation is a stable form of epigenetic modification that reduces gene transcription. The glucocorticoid receptor (GR), which regulates neuroendocrine function through a negative feedback mechanism and contributes to the modulation of immune function, has been the topic of most research on this subject. There is great interest in developing peripheral blood biomarkers of risk for disorders. Abnormalities of endocrine and inflammatory function in peripheral blood can shed light on stress-related immune, vascular, and metabolic abnormalities, and there is some evidence of correspondence between peripheral and central gene regulation for some genes. Multiple genes in the glucocorticoid and inflammatory-signaling pathways are likely involved in the response to childhood adversity. Data on effects of stress exposure on adrenocortical function in MDD and PTSD are mixed with respect to the nature and direction of effects. Studies of the long-term consequences of childhood adversity in adults are limited by recall and judgment biases, a mixture of types of maltreatment, and lack of data on developmental timing. In addition, variability in the literature on adrenocortical function in MDD and PTSD necessitates a greater understanding of the nature of phenotypes and mechanisms involved. The goal of this proposal is to study the effects of chronic childhood adversity on endophenotypes including methylation of genes in the glucocorticoid and inflammatory-signaling pathways, basal and provoked measures of neuroendocrine and immune function, and glucocorticoid receptor sensitivity, as well as phenotypes including measures of coping and behavioral/emotional responses to stress, depressive and anxiety disorder symptoms and diagnose, and measures of somatic symptoms and health. These measures will be tested in a clearly articulated model to yield specific knowledge about the mechanisms of risk for stress-related disorders.